JPH0733642A - Composition used for osmotic pressure delivery device - Google Patents

Abstract

PURPOSE: To obtain a composition for a device of administering a useful medicine at a pulse rate, especially at a pulse rate combined with a zero order delivery rate. CONSTITUTION: This composition contains salbutamol and sodium chloride and is useful for administering the sulbutamol at a pulse delivery rate after an essentially zero order delivery from an osmotic delivery device.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is interrupted while a beneficial agent is pulsed (i) at a controlled pulse rate followed by a constant rate (ii) at increasing doses of beneficial agent. At a substantially constant rate, (iii) at a substantially constant rate followed by terminal pulse delivery of increasing amounts of beneficial agent, and / or at a substantially zero order from the osmotic equipment following the terminal pulse. Outgoing (Zero order deliver
y) Compositions for use in permeabilizing devices for delivery in time.

[0002]

BACKGROUND OF THE INVENTION Permeability delivery devices, which are manufactured as permeation delivery devices for the delivery of useful drugs, are becoming an increasingly important product. These osmotic delivery devices have wide application in industries such as pharmaceuticals, veterinary medicine, and agriculture. The osmotic device used in these industries exhibits a substantially constant beneficial drug delivery rate once the thermodynamic steady state is established by the device. If the thermodynamic activity of the beneficial agent can be maintained substantially constant within the device, a steady state will be established and the rate of drug delivery from the device will be constant over time. This is the term proposed by physico-chemical kinetics, which is the zero order delivery (Zero order re
It is commonly called "lease".

The osmotic device described above represents a significant advance in the zero-order delivery device industry for the continuous and constant controlled rate dispensing of useful drugs. It was unexpectedly found that pulsatile administration of drug delivery provided therapeutic results. For example, low pulse doses of estradiol suppress the secretion of gonadotropins,
Stimulating an ovulatory surge of gonadotropin secretion at high pulse doses is described by Dragus, 23: 2.
07-226, reported in 1982. Therapeutic agents that can obtain beneficial medical effects in this way are pulsed methylprednisolone in collagen, progressive filamentous nephritis; cyclophosphamide-vincristeine-adriamycin in patients suffering from neuroblastoma. Pulsed administration of rifampicin in Hansen's disease; artificial induction of labor by pulsed administration of oxytocin; pulsed administration of insulin for the prevention of hyperglycemia, etc., in Fertil. and Steril . Vol. 39, 6
95-699, 1983: Vtr. Boles.
21: 65-74, 1982: Br. J. Can
cer. Volume 45, pages 86-94, 1982; Fet.
il. and Steril. , Volume 36 553-55
9, 1981; Int. J. Radiat. Onc
ol. Biol. Phys. Volume 8, Pages 915-919,
1982, J. Clin. Endocrinol. M
etab. 53, pp. 184-191, 1981 and Diabetes. Vol. 26, pp. 571-581, 19
Reported in 1977.

To date, there have been no prior art devices that deliver useful drugs at pulse rates, particularly pulse rates in combination with zero order delivery. Therefore, as in the examples given above, those skilled in the pharmaceutical industry can (a) proceed with the pulsing of a useful drug and (b) interrupt with the pulsing of a drug.
(c) Terminal pulse delivery of drug or (d) Substantial constant delivery from the osmotic device following terminal pulse delivery,
It will be readily appreciated that there is an urgent need for a delivery device that is capable of delivering a useful drug at substantially zero order velocity. Moreover, such a device is a new and useful device that can deliver a drug at a constant rate and a pulse rate, and such a device has obvious value and valuable contribution to the dispensing industry. Will also be recognized by those skilled in the art.

[0005]

Therefore, in view of the above description, there is provided a novel useful device capable of delivering a useful drug at a controlled rate accompanied by pulse delivery of an increasing amount of the useful drug at a certain time. It is a direct object of the present invention to provide a composition for use.

Another object of the present invention is to provide a controlled rate with time-determined pulsing when thermodynamic conditions have been established that allow pulsing of a useful drug in an osmotic delivery device. To provide a composition for use in an osmotic delivery device capable of delivering a useful pharmaceutical product of

Yet another object of the present invention is to maximize the delivery of a drug at a controlled rate at a constant concentration for a period of time, accompanied by a pulsed delivery of the drug to achieve the optimum effect of the drug. To provide a composition for a therapeutic method with a medicinal agent, which allows the use of an osmotic device to achieve a therapeutic effect.

Yet another object of the present invention is to administer a drug concentration within the therapeutic range that is effective for the minimum period required for treatment, followed by pulsing administration required for the final therapeutic treatment. It is to provide a composition for an osmotic delivery device for a drug capable of delivering a drug.

Yet another object of the present invention is a composition for an osmotic delivery device which administers a beneficial agent at a pulse rate and subsequently delivers the beneficial agent at a substantially zero order rate over an extended period of time. It is to provide things.

Yet another object of the present invention is a composition for an osmotic delivery device having a dosing regimen involving constant drug delivery with a number of pulses of drug delivery, a complete pharmaceutical regimen for humans. Can be used in a method of dispensing pharmaceuticals, the use of which is to provide a composition for a device which requires manpower only at the beginning and optionally at the end of treatment.

Still another object of the present invention is for an osmotic delivery device for pulsing a useful drug from the osmotic device to a terminal and then dispensing a useful drug having a substantially zero order rate delivery period. It is to provide a composition.

Yet another object of the present invention is to provide a zero order rate delivery to provide an increased amount of drug to a patient who requires additional drug at certain times of the day or night to maintain an appropriate therapeutic effect. It is an object of the present invention to provide a composition for an osmotic delivery device which is characterized by a zero order rate drug delivery which allows for delayed drug delivery in an amount greater than that delivered by the device.

Another object of the present invention is for use in pulsed administration of a useful drug to increase the extent of absorption from the dosage form at the end of treatment following zero order rate delivery of the useful drug. It is to provide a composition.

Other objects, features and advantages of the invention will be apparent to those skilled in the pharmaceutical arts upon reading the specification of the invention in connection with the claims.

[0015]

The present invention is based on the unexpected finding that a composition is obtained for use in an osmotic delivery device having a controlled delivery rate profile. In the present invention, an osmotic agent that delivers a beneficial agent by delivery of a substantially zero order rate for a period of time adjusted to time-dependent pulse delivery of an amount of the useful agent that is greater than the zero order rate delivered from the osmotic device. A composition is provided for use in a pressure device. The zero-order delivery is adjusted by a pulse delivery preceding this zero-order delivery, or by a zero-order delivery adjusted by a pulse delivery interrupting the zero-order, or the adjusted pulse is generated at the terminal of the zero-order delivery. It can also be adjusted by moving to the zero-order delivery following the terminal pulse. This unique delivery rate is obtained by loading an osmotic device with a composition containing a useful agent and a modulator. The modulator is present in the two agents in an amount such that it initially falls below saturation in the osmotic device. When this occurs, the solubility of the useful agent increases, with a concomitant increase in the amount of the useful agent delivered, providing pulsed delivery to the device.

Compositions containing useful agents and modulators are delivered by a osmotic device manufactured as an osmotic device. The permeation device includes a wall that surrounds and defines the Compartment. This compartment contains both a unit dosage of the useful agent and an effective amount of the modulator. This compartment optionally contains formulation ingredients used for ease of manufacture and for controlled delivery. A passageway in the wall communicates between the exterior of the permeabilizer and the compartment for delivery of useful drug from the permeator.

The walls of the osmotic device are formed of a semipermeable composition that does not adversely affect the beneficial agents, modifiers and environment of use. The wall is formed of a semipermeable composition that is permeable to external fluids such as water and biological fluids, but impermeable to useful agents, regulators and other components present in the compartment. Selectively permeable polymers useful for the manufacture of this osmotic device include cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ethers, cellulose acylates, cellulose diacylates,
Represented by a member selected from the group consisting essentially of cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, and cellulose acetate butyrate. Suitable semipermeable polymers useful in the manufacture of osmotic devices are described in US Pat. No. 3,845,845.
No. 770, No. 3,916, 899, No. 4,000
8,719, 4,036,228 and 4,
No. 111,210. These patents
This patent has been assigned to the assignee of this patent application, ALZA, Inc. of Palo Alto, Calif.

In one aspect, the permeabilizer wall is a laminate having a semipermeable membrane in a layered assembly having a microporous membrane. The semipermeable thin film is formed from the above polymer. The microporous thin film includes a plurality of micropores for allowing an external fluid to enter the permeation device and micropaths for communicating with each other. In addition to the polymers described above, the microporous membrane is a pore former that dissolves or leaches from the membrane when using a osmotic device in a biological fluid environment.
The enclosure of r) is included. Pore formers are non-toxic and they do not react with the material forming the microporous membrane. Removal of the pore-forming agent results in fluid-filled passages that cooperate with the semipermeable membrane to mediate fluid entry into the osmotic device. Typical pore forming agents are sodium chloride, potassium chloride, sorbitol, mannitol polyethylene glycol, hydroxypropyl methylcellulose and hydroxypropyl butyl cellulose. An osmotic pressure adjusting device having a laminated wall of a semipermeable thin film and a microporous thin film is disclosed in U.S. Pat. No. 4,160,452 assigned to Alza. In another aspect, the osmotic device has an outer surface coated with a dye-containing coating. This coating is non-toxic, water-soluble and contains a non-toxic dye. This coating can be coated on the semipermeable wall or on the laminated film. For example, this coating consists of a mixture of hydroxypropyl methylcellulose and lake dyes, which are approved by the Food, Pharmaceutical and Cosmetics Act as pharmaceuticals.

As used herein, the representation of passages for a seepage device includes mouths, orifices, lumens, holes, etc. having a seepage dimension through the wall. This expression also
Also included are erodible elements in the membrane, such as gelatin plugs, which erode the permeable passages during environmental use. A detailed description of the seepage passage and the maximum and minimum dimensions for the seepage passage can be found in US Pat. Nos. 3,845,770 and 3,91.
No. 6,899. These patents are assigned to Alza.

The compartments of the osmotic device contain a non-equilibrium ratio of useful agents and regulators. Prior to the present invention, the compartments were included, for example, such that the useful agent and the osmotic agent were present in a ratio indicating mutual solubility between both components within the compartment. In the present invention, the useful agent and modulator are present in a non-equilibrium ratio. The modulator, which optionally acts as an inhibitor of a useful drug, called an insolubilizer, is first used in an amount sufficient to be the first of the two drugs to fall below saturation. At the same time as this thermodynamic result, the solubility of the useful drug is increased, thereby increasing the delivery of the useful drug at the moment of the pulse.

The solubility of useful drugs decreases when they are co-dissolved with the modulator. More particularly, this process occurs due to the presence of fluid entering the compartment through the semipermeable membrane, thereby reducing the solubility of the useful drug in the presence of the incoming fluid. In normal co-solubilization, the beneficial agent and the osmotic agent are in equilibrium and the delivery rate distribution exhibits the traditional pattern as seen in Figures 1a and 1b. In Figures 1a and 1b, the delivery profiles of the useful drug on line a and the modulator on line b are both linear for a period of time and then a and b in the liquid in the compartment.
And both of them decrease as the concentration decreases below saturation. In the present invention, non-equilibrium ratios are typical for co-solubilization of useful agents and modulators, and delivery rate distributions are shown in Figures 2a and 2b. In Figure 2a, the concentration of modifier b is lower than the equilibrium ratio in the compartment and is therefore consumed earlier than the useful agent a is exhausted. As a result, the solubility of the useful agent a increases rapidly in the sub-saturating modifier solution and the delivery rate of the useful agent actually increases as seen in Figure 2b. Further reductions in modulator concentration will result in a pair of delivery rate distributions as shown in Figures 3a and 3b. FIG. 3a shows a diagram when the concentration of modulator b was decreased, and FIG. 3b shows the delayed delivery of a useful drug as a result of the decrease in modulator concentration. From the foregoing description, the present invention provides a seepage device for programming the desired time of useful drug delivery, delayed delivery, and delayed pulse delivery, both of which can be accomplished by adjusting the concentration of the modulator within the seepage permeability device. And it becomes clear that a method is provided.

The timing of pulsing a useful drug is
It is a function of the amount of regulator and the properties of the osmotic system. The timing for starting pulse transmission is as follows:

[Equation 1]

Where T is the time to begin pulsing; Mo is the weight of modifier initially present in the permeabilizer; h is the thickness of the semipermeable wall. ; St is
Solubility of modulator and useful agent in the osmotic device; p is the density of the total mass in the osmotic device; So
Is the mutual solubility of the modifiers in the aqueous medium; ΔIIt
Is the total osmotic pressure generated by both the modulator and the beneficial agent in the osmotic device; K is the permeability of the semipermeable wall; A is in the osmotic device compartment. Is the total surface area of the compressed mass).

Agents which are described herein as useful agents are algicides, air purifiers, antioxidants, biocides,
Catalysts, chemical reactants, cosmetics, pharmaceuticals, disinfectants, fungicides, fermentants, foods, food supplements, antifertility agents, fertilization promoters, fungicides, herbicides, insecticides, microbial attenuators , Nutrients, insecticides, plant growth promoters, plant growth inhibitors, preservatives, contraceptives, sterilants, vitamins and other agents useful for environmental use.

In the present specification and the appended claims, the term drug is used for warm-blooded animals, mammals,
Included are any physiologically or pharmacologically active substances that exert a local or systemic effect on animals including humans, primates, birds, reptiles and fish. Also in the word animal,
Includes domestic animals, sports and domestic and medicinal and research animals such as sheep, goats, cats, cows, horses and pigs, jungle animals and zoo animals. Active drugs include hypnotics, sedatives, psychostimulants, tranquilizers, stimulants, anticonvulsants, muscle relaxants, anti-Parkinson's agents, analgesics, anti-inflammatory agents, anesthetics, without limitation inorganic and organic compounds. Muscle contractors, anti-infective agents, bactericidal agents, antimalarial agents, hormone agents, sympathomimetic agents, metabolic dysfunction agents, diuretics, anthelmintic agents, neoplastic agents, hypoglycemic agents, nutritional agents,
Included are drugs that act on the central nervous system such as fats, eye drops, eluents, stimulants and diagnostics. The aforementioned drugs are peripheral nerves, adrenergic receptors, choline receptors, nervous system, skeletal muscle, cardiovascular, smooth muscle, blood circulation system, synaptic site, neuroeffector junction site, endocrine and hormone system, hypersensitivity system, reproductive organs. System, skeletal system,
It acts on the local hormonal system, the digestive system, the excretory system, the local hormone and histamine inhibitory system, and the central nervous system, which all act. The amount of useful agent present in the osmotic device is generally in dosage unit amounts for providing the desired therapeutic effect. This permeation pressure device is generally 0.05 ng
Can contain ~ 5g or more, eg 25ng, 1
mg, 5 mg, 50 mg, 100 mg, 125 mg, 250 mg, 5
Individual devices containing 00 mg, 750 mg, 1.5 g, etc. are included.

Modulators useful for the purposes of the present invention include ionized compounds, naturally polar compounds, inorganic acids, organic acids,
It is soluble in aqueous and biological fluids such as bases and salts and salts containing ions common to drugs. In a preferred embodiment, the compound is a solid and dissolves in the fluid entering the osmotic device to form a solution. Examples of inorganic salts include lithium chloride, lithium sulfate, magnesium chloride,
It is a member selected from the group consisting essentially of magnesium sulfate, potassium chloride, potassium sulfate, potassium hydrogen phosphate, sodium chloride, sodium sulfate, sodium sulfite, sodium nitrate, sodium nitrite, and the like. The salt of the organic acid is a member essentially selected from the group consisting of sodium citrate, potassium hydrogen tartrate, sodium hydrogen tartrate and the like. Therapeutically acceptable salts which have ions in common with the useful agents are sodium chloride and sodium indomethacin; triflupromazine hydrochloride and sodium chloride; or phenelzine sulfate and sodium sulfate.
Ionizable solid acids useful as regulators are members selected from the group consisting essentially of tartaric acid, citric acid, maleic acid, malic acid, fumaric acid, tartronic acid, itaconic acid, adipic acid, succinic acid, mesaconic acid and the like. Represented by The basic compound is represented by a member selected from the group consisting essentially of potassium carbonate, sodium carbonate, ammonium carbonate and the like.

During the non-zero order velocity period from the penetrator,
The concentration of modifier in the permeator is given by equation 1.

[Equation 2]

Where Co is the concentration of the regulator in the permeator during the non-zero order period; Vt is the total internal volume of the permeator; Zo is the zero order of the regulator. Delivery rate; So is the solubility of the regulator; t is the time at the start of delivery and tz is the zero order delivery time of the regulator). 4a.

On the other hand, the solubility of the useful drug is such that the concentration Cd of the useful drug in the osmotic device decreases as the concentration Co of the modifier approaches 0 or decreases as Co → 0. Is equal to the solubility Sd in water, and Cd = Sd, which is a large value. Further, when the concentration Co of the regulator is equal to the saturation concentration So of the regulator, the concentration Cd of the useful drug becomes equal to the concentration S ° d of mutual solubility between the useful drug and the regulator, that is, Cd = S. This results in a small value of ° d, which is shown in Fig. 4b. Table I shows that various concentrations of the regulator NaC
useful drugs in 1
The experimental data of the solubility of (mol) are shown.

When the concentration of modulator is exhausted over time, the concentration of useful drug decreases monotonically between these two limits. The delivery rate of the useful drug from the seepage device is represented by equation 2.

[Equation 3]

Where (dm / dt) d is the useful drug delivery rate; K is the water permeability of the semipermeable membrane;
A is the surface area of the osmotic device; h is the thickness of the semipermeable membrane; Cd is the concentration of the useful drug in the osmotic device; πt is the useful drug and the modulator. Is the osmotic pressure generated by the formulation).

As Co continuously decreases according to Equation 1, Cd increases from a small value S ° d to a large value Sd,
As a result, (dm / dt) d is increased by the equation 2, and FIG.
c [(dn / dt) o in the figure is the delivery speed of the regulator]
As can be seen from the above, a pulse is generated in the delivery form. In this permeation pressure device, the total driving force for drug delivery is πtCd.
Is the product of πtCd is maximal at certain concentrations of modulator. In the example shown in Table 1, the peak of the pulse is about Co.
/ So≈. It's happening at 38. Thus, the modulator: useful drug ratio, R, is any value of 0 <R <(So / Sd) where So / Sd is the mutual solubility of the useful drug in the modulator.

Useful agents and modifiers can be present in the compartment in admixture with binders, dyes, lubricants, dispersants and formulation ingredients. Dispensing ingredients include binders such as poly (ethylene glycol), gelatin, agar, carboxycellulose, poly (vinyl alcohol) and poly (vinylpyrrolidone). Typical lubricants include stearic acid, magnesium stearate, zinc stearate, aluminum stearate, halogenated vegetable oils and talc. In the compartment,
A disintegrant can be included to dissolve the agent and modulators useful in facilitating controlled delivery from the osmotic device into a solution. Typical disintegrants include lightly cross-linked poly (vinylpyrrolidone), corn starch, potato starch, Veegum,
Includes pentonite and citrus pulp. Coloring agents include non-toxic dyes such as Blue No. 1 in Lactose, which is approved by the Food, Drug and Cosmetics Act. If desired, the dye in the compartment and the dye in the wall can be the same or different. The amount of binder, lubricant or disintegrant is usually about 0.0 each of the total weight present in the compartment.
It is 1% to 20%.

The osmotic device of the present invention containing useful agents, regulators and other ingredients can be manufactured by standard manufacturing methods. For example, in one embodiment, the useful agent is mixed with the modifier and other compartment core components in a non-equilibrium ratio to round these components into spheres, rolling, stirring,
The pressurization brings it into a predetermined shape according to the shape of the final permeation device. The material forming the walls of the device can be applied to the pressurized formulation by impregnation, molding or spraying. One method of applying semipermeable walls or laminated walls is air suspension.
procedure). This method can form a single-layer wall or a laminated wall composed of two layers. The air suspension method is described in US Pat. No. 2,799,241, J.
Am. Palm. Assoc. Volume 48, 451-45
P. 9, 1959 and the same magazine , vol. 49, pp. 82-84,
It is described in 1960. The seepage passage can be made by mechanical drilling, laser drilling, and die stamping or cutting. A method of forming a passage using a laser is disclosed in U.S. Pat. Nos. 3,916,899 and 4,082, both assigned to Alsa.
No. 8,864. Osmotic delivery devices designed for oral administration can also be in the form of rounds of diameter 3/16 "to 9/16" or solid capsules in the range of 0-0 and 1-8 sizes. . These shapes provide the osmotic device with a size and shape suitable for administering useful drugs to warm-blooded animals, including humans. Other standard equipment manufacturing methods are modern plastic
Qu Encyclopedia Vol. 46, pp. 62-70, 1
969; Remington Pharmaceuticals Sayer
Nsu 14th Edition, 1649 to 1693 pages; and The Aromatherapy and by Lachman (Lackman), etc.
Practice of K. Industrial Pharmacy
, Pp. 197-225, 1970.

The following examples are merely illustrative of the invention and are not to be construed as limiting the scope of the invention in any way, and these examples and their equivalents are not to be construed as limitations of the invention. It will be further apparent to those skilled in the pharmaceutical industry with reference to the disclosure and the appended claims.

Example 1 β delivered at a constant rate adjusted by the pulse rate
Salbutamol, an adrenergic stimulant and bronchodilator, ie α-
[(T-butylamino) methyl] -4-hydroxy-m
An osmotic therapeutic device for the controlled delivery of -xylene-α, α'-diol-hemisulfate is constructed as follows: first of salbutamol hemisulfate (hereinafter salbutamol) and the regulator sodium chloride. The solubilities were measured in distilled water at 37 ° C. and showed the following solubilities: solubility of salbutamol in water 2
75 mg / ml, solubility of salbutamol in saturated solution of sodium chloride 16 mg / ml, solubility of sodium chloride in water 321 mg / ml, solubility of sodium chloride in saturated solution of salbutamol 320 mg / ml, and salbutamol in saturated sodium chloride The total solubility of the solubility and the solubility of sodium chloride in water is 16 + 320 = 3
36 mg / ml.

A composition containing salbutamol: sodium chloride in a ratio of 1: 5 was then prepared as follows: first 14.45 mg salbutamol 72.30 mg sodium chloride, 1.8 mg crosslinked carboxy. Methylcellulose and 1.8 mg of poly (vinylpyrrolidone) 60
Mix through a mesh screen in a blender for 1 hour. The blended ingredients were then transferred to the larger blender and 8 ml of granulated fluid consisting of 90:10 ethanol: water was added to it and all ingredients were blended for about 20 minutes. The uniformly blended ingredients were passed through a 20 mesh screen and dried in a forced air oven at 50 ° C for 12 hours. After drying, the granules were mixed with 0.9 mg magnesium stearate and blended for 10 minutes. The granules were transferred to a conventional manesty tablet press and compressed with a standard circular 5/32 inch die to a hardness of 1.5-2 kp. The area of this compressed drug core is 0.
It was 41 cm ² and weighed 91.3 mg.

The compressed core is treated with an Aeromatic.RTM. Air suspension coater (air suspension c).
and a wall made of cellulose acetate with an acetyl content was coated around the core. This semipermeable wall has 42.5% (1%) with an acetyl content of 39.8%.
2.75 g) cellulose acetate, methylene chloride-
Cosolvent consisting of methanol 80% -20% (588 ml)
-256 ml) containing 15% (4.5 g) of hydroxypropylmethylcellulose. After forming walls around the reservoir, they were transferred into a forced air oven and dried at 50 ° C. for 48 hours. Next, a permeable passage of 0.25 mm diameter was laser drilled through the semipermeable wall. The weight of this semipermeable wall was 5.9 mg.

The osmotic delivery device for useful drugs prepared in this example is shown in FIGS. FIG. 5 shows a permeation device having a main body 11 having a passage 12 that connects the inside and the outside of the permeation device 10. FIG. 6 shows an incised cross section at 13 of the device 10 and includes a semi-permeable wall 14 surrounding and defining the internal compartment 15. Compartment 15 contains the beneficial agent salbutamol 16, the regulator sodium chloride 17 and other pharmaceutical ingredients. 7 to 9 are shown in FIG.
Figure 3 shows a delivery rate profile consisting essentially of a 7 hour zero order rate delivery adjusted by pulsing delivery of time useful agent.
FIG. 8 shows the cumulative dose of the useful drug salbutamol delivered over 12 hours. The bars in FIGS. 7 and 8 show the maximum and minimum amount of delivery during the measurement.

Example 2 Salbutamol at a constant rate interrupted by pulse rate delivery and the bronchodilator terbutaline sulfate, 1-
An oral osmotic device for controlled co-delivery of (3,5-dihydroxyphenyl) -2- (t-butylamino) ethanol was made as follows: first 9.64 mg salbutamol, 5 mg terbutaline sulfate. , 24 mg sodium chloride, 0.71 mg poly (vinylpyrrolidone) and 0.71 mg crosslinked carboxymethylcellulose were blended and passed through a 60 mesh screen. The salbutamol: sodium chloride ratio in the composition is 1:
It is 3. A granulated liquid consisting of 90:10 ethanol: water was then added to the screened blend and all ingredients were blended for about 15-20 minutes. The well blended ingredients were passed through a 30 mesh screen and dried in a forced air oven at 50 ° C for 12-15 hours. After drying, the granules were mixed with 0.35 mg stearic acid and blended for 10 minutes. This blend was then pressed into the pre-compartment form drug formulation. The compressed drug formulation was placed in an air suspension system and coated with the microporous film forming composition.
The composition for forming a microporous thin film has an acetyl content of 39.8.
% Cellulose acetate 49% by weight, 28.5% by weight hydroxypropylmethylcellulose and 22.5% by weight
Of polyethylene glycol 4000. This thin film was formed using methylene chloride-ethanol (95%) thin film solvent (80:20 wt: wt). This microporous thin film has a thickness of 0.12 mm.

Next, an outer semipermeable membrane was laminated on the microporous thin film in a conventional air suspension device. The composition for forming a semipermeable membrane was composed of 90% by weight of cellulose acetate having an acetyl content of 39.8% and 10% of cellulose acetate having an acetyl content of 32%. This semipermeable membrane was applied to a laminated structure using a solvent mixture consisting of methylene chloride and ethanol (80:20 wt: wt). The permeator was dried and a 0.26 mm diameter passage was drilled through the laminate wall using a laser. In FIG. 9, a main body 11, a passage 12, an open cross section 13, an outer semipermeable wall 14, an inner compartment 15,
Salbutamol 16, sodium chloride 17, inner microporous wall 18 and terbutaline 19 are shown.

Example 3 Hydroxyl-oxprenolol-H
An osmotic device for controlled and continuous delivery of oxprenolol hydrochloride by pulsing Cl) was prepared by the general method described above. In the permeation apparatus of this example, 1 part of oxprenolol hydrochloride and 6 parts of potassium chloride: sodium chloride (50:
50) contains a drug formulation consisting of a non-equilibrium formulation of the mixture. This compartment also contained 2 mg dextrose, 2 mg potato starch and 3 mg magnesium stearate. After compression, this formulation has a diameter of 9 mm. This device has an acetyl content of 43.5%
And 60% by weight of cellulose acetate having a degree of substitution of 3 and 39.8% of acetyl content and cellulose acetate having a degree of substitution of 2.4
It has a laminated wall consisting essentially of 0%. The semipermeable membrane is applied with a solvent consisting essentially of a 80:20 weight ratio of methylene chloride and methanol. This device uses cellulose acetate 5 with an acetyl content of 39.8%.
5 wt% and 35 wt% sorbitol and 10 wt%
With an outer microporous membrane consisting essentially of polyethylene glycol 400 of. This film is applied using a solvent consisting of 90:10 by weight methylene chloride-methanol. This semipermeable thin film has a thickness of 0.12 mm,
The thickness of the microporous thin film is 0.13 mm. This device has a 0.25 mm passage.

Example 4 In this example, a salbutamol: sodium chloride ratio of 1:
7 and the permeator compartment had 9.6 mg salbutamol sulfate, 56 mg sodium chloride, 1.4 mg poly (vinylpyrrolidone), 1.4 mg cross-linked sodium carboxymethyl cellulose and 0.6 mg stearin. The method of Example 1 is repeated to make a osmotic device containing a drug formulation consisting essentially of magnesium acid salt. This device delivers salbutamol for 12 hours.
0 with a terminal pulse delivery of salbutamol. The seepage permeable device has a 4.9 mil (0.13 mm) thick semipermeable wall of the semipermeable wall composition of Example 1.

Example 5 A osmotic device is made by the method of Example 1 with a salbutamol: modulator sodium chloride ratio of 1: 9. 28.9 mg of salbutamol sulfate,
Included is a pharmaceutical formulation consisting essentially of 216 mg sodium chloride, 5.2 mg poly (vinylpyrrolidone), 5.2 mg cross-linked sodium carboxymethyl cellulose and 2.6 mg magnesium stearate. The seepage permeable device has a 20.1 mg weight semipermeable wall containing the composition of Example 1. The device has 16 hours of zero-order delivery of salbutamol followed by 8 hours of increased salbutamol delivery. A 24-hour delivery diagram of this permeation pressure device is shown in FIG.

Example 6 Acebutotol for Gastrointestinal Administration
ol) An oral osmotic device for α, β-adrenergic blocking agent is manufactured in the following size and shape: 10 parts acebutotol hydrochloride and 90 parts potassium carbonate, 8.7.
Mix 5 mg of uncrosslinked poly (vinylpyrrolidone),
1 at room temperature through a 0 mesh stainless steel screen
Blend for hours. The blended ingredients are then transferred to a large blender and 40 ml of granulated liquid consisting of a 90:10 volume ratio of ethanol: water is added to the blender and the ingredients are blended for 20 minutes. The fully blended ingredients are passed through a 30 mesh screen and dried in a forced air oven at 50 ° C for 16-17 hours.

The dried granules are then passed through a 20 mesh screen and 5 mg magnesium stearate is added. The ingredients are blended for 15 minutes and the blended granules are transferred to a conventional Manestie Press. This component is compressed into an acetoutol reservoir with a diameter of about 6 mm.

The above composition for forming the acebutotol precompartment is transferred to an air suspension coater and surrounded by a semipermeable wall. The semipermeable wall is formed from a wall forming composition containing 35 g of cellulose acetate having an acetyl content of 39.8% and an organic solvent consisting essentially of 550 ml of ethylene chloride and 110 ml of methanol. After forming a semi-permeable wall around the drug reservoir, it is placed in a forced air oven at 50 ° C. for 50 minutes.
Let dry for hours. A 0.4 ml passage is then lasered through the semipermeable wall for communication between the exterior of the permeator and the interior of the compartment. The weight of this semi-permeable wall is 8.6 mg,
The device delivers 12 hours of drug controlled by end pulse delivery.

EXAMPLE 7 The procedure of Example 1 is repeated to make a osmotic device to produce a device where the useful drug salbutamol: modulator ratio is 1: 9 and pulse delivery occurs near the middle of the delivery pattern. In Example 7, the osmotic device was 9.3 wt% salbutamol, 1.9 wt% as the hemisulfate, 83.8 wt% sodium chloride, 2 wt% cross-linked sodium carboxymethyl cellulose, 2 wt%. % Polyvinylpyrrolidone and 1% by weight magnesium stearate. The device has a semipermeable wall consisting of 42.5% by weight cellulose acetate with an acetyl content of 39.8%, 42.5% by weight cellulose acetate with an acetyl content of 32% and 15% by weight hydroxypropylmethylcellulose. The passage diameter is 0.25 mm, the semipermeable wall weighs 4.8 mg and the wall thickness is 0.06 mm. FIG. 12 shows the measured delivery pattern of this permeation pressure device, and FIG. 13 shows the cumulative amount delivery.

Presently preferred embodiments of the present invention are: (A) (a) allow passage of external fluid but are substantially impermeable to the passage of drug and modulator surrounded by and forming a wall. A wall formed from a non-toxic semipermeable composition that is: (b)
A compartment containing a unit dose of a medicament and an effective amount of the modulator, which is a modulator that serves to deliver the pulse of the medicament; and (c) outside the permeabilizer and inside the permeator. An oral osmotic device containing a passageway in the wall for communicating with the patient, shaped and dimensioned for the patient's gastrointestinal tract and determined by (B) permeability of the semipermeable membrane and osmotic gradient of the semipermeable membrane. Accepts an external fluid entering the compartment through the semipermeable membrane at a rate that is defined by hydrodynamic and osmotic pressure to form a solution containing the drug delivered from the osmotic device, via the (C) passage. Then, a therapeutically effective amount of the drug is delivered at a substantially constant rate to the patient's gastrointestinal tract with a pulse delivery of an effective amount of the drug over a certain amount, and the drug is delivered at a constant rate and a pulse rate for a long time. A pharmaceutical package consisting of obtaining the desired beneficial effect of administration. Scan is a method of supplying a medicament constant controlled rate by the feed.

This permeation device is an implant (impl)
can also be used as an ant), or a conduit can be connected to the passageway for intravenous administration of the drug or subcutaneous administration of the drug. Drugs delivered at zero-order rate with pulse rate, controlled, substantially constant salbutamol delivery method with pulse delivery of salbutamol; controlled acebutolol with time-dependent pulse delivery of acebutolol A method of delivery; a method of treating asthma that provides a beneficial effect to a patient suffering from asthma by administering to the patient suffering from asthma a therapeutically effective amount of salbutomol in a constant amount interrupted by a pulse rate dose of salbutomol. Salbutamol and acebutolol are also administered in a manner that causes bronchodilation in patients who require bronchodilators, especially for acute and chronic patients. The useful agents are delivered at a controlled continuous rate over a period of 15 minutes to 24 hours with an intermediate pulse of 15 minutes to 24 hours or pulsed terminal.

In accordance with the present invention, there is provided an osmotic treatment device manufactured in the form of an osmotic device for creating an improved drug delivery program. While the novel features of the invention have been set forth and pointed out as the presently preferred embodiments, those skilled in the art can make various modifications, alterations and omissions of the invention as illustrated and described without departing from the spirit of the invention. Will be recognized.

[0052]

[Table 1]

[Brief description of drawings]

FIG. 1 is a delivery rate diagram for normal co-solubilization where the beneficial agent and the modulator are in equilibrium in the compartment, where the beneficial agent is line a and the modulator is line b.

FIG. 2 is a delivery rate diagram for co-solubilization where the beneficial agent and the modulator are present in non-equilibrium ratio, line b is the modulator and line a is the useful agent.

FIG. 3a is a graphic representation of modulator delivery rate as the concentration of modulator b is decreased. FIG. 5b is a delayed delivery rate diagram of a useful drug with a decrease in the concentration of the modulator.

FIG. 4 a is a delivery pattern of the modulator of Formula 1. b is Cd
FIG. 9 is a relationship diagram between the useful drug concentration Cd and the regulator concentration Co when the value of S = d is small. c indicates a pulse when Cd increases from S ° d (small value) to Sd (large value) with the continuous decrease of Co, and the value of (dm / dt) d increases according to the equation 2. In the figure, (dm / dt) o is the delivery rate of the regulator.

5 is a permeation pressure device 10 manufactured according to Example 1. FIG.

6 is an open sectional view of the permeation pressure device 10 at 13. FIG.

FIG. 7 is a zero-hour delivery pattern of 7 hours adjusted by pulse delivery of 7-9 hours by the above device.

FIG. 8 illustrates cumulative delivery over 12 hours.

FIG. 9 is a sectional view of the permeation pressure device 10 according to the second embodiment.

FIG. 10 is a delivery diagram with pulse delivery at the end.

FIG. 11 is a 24-hour delivery graphic.

FIG. 12 is a measured delivery pattern of the permeation device according to Example 7.

FIG. 13 is a measured cumulative delivery figure of the permeation pressure device according to Example 7.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Patrick S. Elle. Wong United States Hayward, Calif., USA, Xavier Avenyu 1371 (72) Inventor Hueritzkus Sewes, Los Altos, Calif., Fowloon Reef Lane 1643

Claims (1)

[Claims] 1. A composition comprising salbutamol and sodium chloride which is a composition useful for dispensing salbutamol in pulse rate delivery after delivery of a substantially zero order rate from an osmotic delivery device.